When COPD patients in a prospective Danish study had high levels of C-reactive protein (CRP), serum fibrinogen, and leukocyte count, their risk of experiencing a disease flare during the following year was increased by a factor of 2.5 (95% CI 1.8-3.4) compared with patients who did not have high values for any of these measures, according to Børge Nordestgaard, DMSc, of Copenhagen University Hospital in Denmark, and colleagues.

The 5-year risk for exacerbations was 62% in patients with GOLD grade C-D disease and who had high baseline values for the three biomarkers, versus 24% among those with no high biomarkers, the researchers reported in the June 12 issue of the Journal of the American Medical Association.

But the biomarkers appeared to have their greatest clinical value when levels were low -- such patients were at significantly lower risk for developing frequent exacerbations than would be expected from conventional predictors, such as previous exacerbation history and objective measures of lung function.

In an accompanying editorial, two U.S.-based researchers said the study "adds to the growing interest in systemic inflammation in COPD and its negative consequences."

M. Jeffery Mador, MD, and Sanjay Sethi, MD, both of the State University of New York at Buffalo, also noted that the three biomarkers "are simple to measure, inexpensive, and readily available," and that the study provided specific cutoff values for them.

Another respiratory disease specialist, Elizabeth Regan, MD, PhD, of National Jewish Health in Denver, told MedPage Today that the findings could have short-term clinical implications.

"[Physicians] can incorporate this into their practices and use [the test] as a way to identify people who are at higher risk for developing exacerbations," she said. "I would hope that physicians would start looking at their COPD patients and try to assess whether or not they are high risk by going ahead and doing these relatively straightforward tests."

Additional treatments could be considered for patients with high levels of the three markers, Regan said.

In the current work, Nordestgaard and colleagues analyzed data on patients with COPD who had participated in two observational studies, the Copenhagen City Heart Study and the Copenhagen General Population Study. Of the more than 60,000 individuals involved in these studies, 6,574 had spirometry-confirmed COPD, did not have asthma, and were at least 40-years-old.

As part of the two studies, participants were tested at baseline for CRP, fibrinogen, and leukocyte counts. Cutoffs defining high levels were 3 mg/mL for CRP, 14 micromol/L for fibrinogen, and 9 billion/L for leukocyte counts. The CRP cutoff was based on standards used previously in cardiovascular medicine, whereas the other two were chosen to approximate the median values among participants included in the analysis.

During median follow-up of 4 years, 3,083 COPD exacerbation episodes were recorded, for an average of 0.5 per patient. For each biomarker found to be high in a given patient, the risk of exacerbation (expressed as a hazard ratio relative to patients with no high biomarkers) increased progressively:

One biomarker: HR 1.4 (95% CI 1.1-1.8)

Two biomarkers: HR 1.6 (95% CI 1.3-2.2)

Three biomarkers: HR 2.5 (95% CI 1.8-3.4)

The P-value for the above trend was vanishingly small at 10-8, Nordestgaard and colleagues reported.

A similar pattern was seen with the risk of frequent exacerbations, defined as at least two during the first year of follow-up, which were seen in 129 patients. Odds ratios adjusted for demographic and clinical variables, again with patients having no high biomarkers as the reference, started at 1.2 (95% CI 0.7-2.2) for those with one high biomarker and ranged up to 3.7 (95% CI 1.9-7.4) for those with three high biomarkers.

Absolute rates of frequent exacerbation ranged from nine per 1,000 person-years in those with no high biomarkers to 91 per 1,000 person-years in patients with three.

The biomarkers' greatest predictive value was when they were found to be low. The positive predictive value of three high biomarker levels was just 8% when used alone for predicting frequent exacerbations, whereas the negative predictive value of three low levels was 99%, the researchers calculated.

But adding the biomarker results to a standard model -- incorporating age, sex, spirometry values, smoking history, use of inhaled medications, body mass index, history of previous exacerbations, and time from the most recent exacerbation -- improved the overall predictive power markedly.

The net reclassification index when biomarker results were included with the other factors was 40% (95% CI 22%-57%, P=8×10-6), Nordestgaard and colleagues reported. This effect, too, largely derived from better identification of patients who did not experience exacerbations.

Limitations included the diagnosis of COPD based on prebronchodilator spirometry alone, a relatively small number of patients with severe COPD, the low exacerbation rate compared with previous studies, and the shift in COPD treatment paradigms during the study period.

In their editorial, Mador and Sethi cautioned that the study population had relatively mild COPD, such that the findings may not be fully generalizable to those with more severe disease.

The study was supported with internal institutional funds and the Danish Heart Foundation.

Study authors and Sethi declared they had no relevant financial interests. Mador reported grants from GlaxoSmithKline and the NIH.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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